Respiratory syncytial virus inhibitors. Part 2: Benzimidazol-2-one derivatives

Article abstract of DOI:10.1016/j.bmcl.2003.12.072

Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of be

Full text of DOI:10.1016/j.bmcl.2003.12.072

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1133–1137
Respiratory syncytial virus inhibitors.
Part 2: Benzimidazol-2-one derivatives§
Kuo-Long Yu,a,y Yi Zhang,a Rita L. Civiello,a Ashok K. Trehan,a Bradley C. Pearce,a
Zhiwei Yin,a Keith D. Combrink,a,{ H. Belgin Gulgeze,a Xiangdong Alan Wang,a
Kathleen F. Kadow,b Christopher W. Cianci,b Mark Krystalb
and Nicholas A. Meanwella,*
aDepartment of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5, Research Parkway,
Wallingford, CT 06492, USA
bDepartment of Virology, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5, Research Parkway,
Wallingford, CT 06492, USA
Received 9 November 2003; revised 14 December 2003; accepted 18 December 2003
Abstract—Structure–activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are
described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of
benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.
# 2003 Elsevier Ltd. All rights reserved.
Respiratory syncytial virus (RSV) infections are com-
mon annual occurrences in the United States that are
largely associated with the winter season, although the
virus can also be detected during the summer
months.2À6 Children are generally exposed to RSV
initially before the age of 2 years and co-infection with
other respiratory pathogens can lead to exacerbated
symptoms.7,8 Infants with underlying cardiopulmonary
problems are particularly susceptible to complications
from RSV infection, which is the most common viral
cause of death in children under 5 years of age.6 More-
over, reinfection with RSV is common in both children
and adults, a consequence of incomplete immunity of
limited durability, whilst the morbidity and mortality
associated with RSV infections of the elderly may be
significantly underestimated since it is frequently mis-
diagnosed as influenza.6,9 The humanized monoclonal
antibody palavizumab (Synagis1), delivered by a series
of injections, is licensed for the prevention of RSV
infections,10 whilst ribavirin, frequently administered by
aerosolization, is the only approved therapeutic agent.11
However, ribavirin is a non-selective antiviral agent and
teratogenic,12 prompting a search for more potent and
selective inhibitors of RSV.2,13 The majority of screen-
ing campaigns have relied upon a virus replication assay
designed to identify leads without bias for a specific
mechanistic intervention. Interestingly, many of the
selective RSV inhibitors that have recently emerged
have been characterized as interfering with the fusion of
virus and host cell membranes.14À20
* Corresponding author. Tel.: +1-203-677-6679; fax: +1-203-677-
7702; e-mail: nicholas.meanwell@bms.com
We have recently profiled the fundamental structure–
activity relationships associated with a new class of RSV
fusion inhibitor, a series of benzotriazole derivatives of
which 1 is representative.1 The diethylaminoethyl side
chain of 1 was found to be quite tolerant towards
§For Part 1 of this series, see ref 1.
y
Current address: Lilly Research Laboratories, Eli Lilly and Com-
pany, Indianapolis, IN 46285-0438, USA.
{
Current address: Cumbre Inc., 1502 Viceroy Drive, Dallas, TX
75235, USA.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.072

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K.-L. Yu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1133–1137
structural variation, with a broad range of polar and
non-polar functionality compatible with RSV inhibi-
tion. The principal requirement related to a minimum 2
atom separation between the terminal functionality and
the benzimidazole heterocycle. As part of a broad sur-
vey designed to delineate the pharmacophore associated
with 1, replacement of the benzotriazole element with a
benzimidazol-2-one was examined as a means of prob-
ing a substituent vector not available to 1.21À24 In this
communication, we demonstrate that simple derivatives
of 2 are potent inhibitors of RSV in vitro and establish a
correspondence with 1.
For 10 in which PG=iso-propenyl, hydrolysis under
acidic conditions removed this protecting group26 whilst
for 10 with PG=CO2Et, mild basic hydrolysis accom-
plished the conversion to 11.25 The iso-propenyl moiety
of 9 or 10 was hydrogenated to afford the corresponding
isopropyl-substituted compounds. Alkylation of the
benzimidazolone nitrogen of 11 was readily accomplished
under the influence of NaH, Cs2CO3 or the phosphazene
base t-butylimino-tri(pyrrolidino)phosphorane (BTPP)
in the presence of an electrophilic halide or mesylate, to
afford target compounds 2. In some cases, the mono-
alkyated benzimidazol-2-one 3 was preformed using lit-
erature procedures25,26 and coupled with 7 to afford 2 in
a more direct fashion. One final avenue exploited the
mesyl moiety as a protecting group for the benzimida-
zole nitrogen atom in 7, a moiety readily removed from
10 using TBAF in THF to give 12. Alkylation of 12
using the same bases utilized to derivatize 11 provided
target compounds 2. The ketone moieties of 2r, s and v
were reduced with NaBH4 whilst acetates 2x and y were
hydrolyzed to the corresponding alcohols using K2CO3
in methanol.
Access to benzimidazol-2-one derivatives 2 was accom-
plished by several complementary pathways, summar-
ized in Schemes 1 and 2. The process selected for
individual targets was dictated by functional group
compatibility or convenience. Alkylation of a mono-
protected benzimidazol-2-one derivative 3 with an ester
of bromoacetic acid was followed by liberation of the
acid moiety (NaOH/MeOH for the Me ester, CF3CO2H
for the t-butyl ester) to afford 4. Activation of the car-
boxylate of 4 using SOCl2 or N-(3-dimethylaminopro-
pyl)-N0-ethylcarbodiimide (EDC) was followed by the
addition of a monosubstituted phenylene diamine deriv-
ative 5. Dehydration of the intermediate amide was
induced by heating in AcOH at reflux to provide target
benzimidazoles 2 (Scheme 1). Alternatively, as depicted
in Scheme 2, alkylation of 2-hydroxymethylbenzimida-
zole (6), using NaH in a mixture of DMF and THF, was
followed by SOCl2-mediated chlorination to afford 7.
The chloride 7 was used as an electrophile for a mono-
protected benzimidazol-2-one derivative, either the car-
boethoxy derivative 825 or the iso-propenyl-substituted
compound 9,26 to provide the protected precursor 10.
The diazirene element incorporated into 2k and m was
examined as a potential photolabelling moiety and
was synthesized using 3,3-azo-l-(methanesulfonyloxy)-
butane27 as the electrophile to alkylate 6, a reaction
mediated by KOtBu in THF.28 Reaction of 8 with 4-
(chloromethyl)phenyl acetate mediated by BTPP in the
presence of (nBu)4NBr followed by saponification pro-
vided the corresponding phenol, which was protected as
its TBDMS ether and coupled with the diazirene-con-
taining chloride 7 using BTPP as the base. The TBDMS
moiety was removed using TBAF in THF to provide
phenol 2k, which was doubly iodinated using NaI and
Scheme 1.
Scheme 2.

K.-L. Yu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1133–1137
1135
Table 1. Structure, RSV inhibitory activity and cytotoxicity associated with a series of substituted benzimidazol-2-one derivatives 2
Compd
R1
R2
Antiviral activity
EC50 (mM)a
Cytoxicity
CC50 (mM)b
Therapeutic
index
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
iso-Propenyl
iso-Propenyl
H
CH2CH3
allyl
CH2CN
0.75 (1.165/0.326)
0.004 (0.005/0.003)
0.057 (0.084/0.030)
0.011 (0.018/0.005)
0.016 (0.010/0.021)
0.028 (0.020/0.018/0.044)
0.040 (0.031/0.049)
0.035 (0.045/0.025)
0.025 (0.018/0.031)
0.018 (0.015/0.021/0.017)
28.4 (30.1/26.6)
24.7 (11.7/37.6)
61.1 (64.5/57.8)
18.6 (28.0/9.3)
38
6175
1071
1690
800
1671
1490
428
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
12.8 (14.8/10.8)
46.8 (18.1/119.1/3.17)
59.6 (39.3/80.0)
15.0 (24.1/5.9)
13.4 (10.3/16.4)
59.9 (49.9/108.5/21.3)
CH2CH2CH2CN
CH2CH2CH2CH2CN
CH2CH2CH2CH2CH2CN
CH2-4-C6H4-OH
536
3327
2j
2k
2l
CH2-4-C6H4-OH
0.004 (0.003/0.005/0.003)
0.686 (0.461/1.378/0.219)
0.038 (0.026/0.088/0.002)
(>220/135.1/112.4)
>144.44 (n=3)
>28,000
>209
713
CH2CH2CH(CH3)2
CH2-3,5-di-I-4-C6H2-OH
CH2-3,5-di-I-4-C6H2-OH
2m
27.13 (27.5/30.0/23.9)
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
2y
2z
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
2aj
2ak
2al
2am
2an
2ao
2ap
2aq
2ar
2as
2at
2au
2av
2aw
2ax
2ay
2az
2ba
2bb
2bc
2bd
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2-4-C6H4-CN
CH2-4-C6H4-CON(CH3)2
CH2-4-C6H4-SO2CH3
CH2-4-C6H4-SO2N(CH3)2
iso-Propenyl
0.012 (0.014/0.010)
0.021 (0.013/0.028)
0.009 (0.013/0.004)
0.004 (0.002/0.006)
0.005 (0.005/0.004)
0.191 (0.184/0.198)
0.028 (0.046/0.01)
0.416 (0.366/0.466)
0.112 (0.062/0.024/0.25)
0.037 (0.041/0.033)
0.018 (0.007/0.029)
0.021 (0.013/0.017/0.035)
0.229 (0.285/0.173)
0.01 (0.009/0.01)
0.004 (0.005/0.004)
0.173 (0.172/0.045/0.303)
0.011 (0.013/0.010)
0.014 (0.004/0.020/0.019)
0.053 (0.093/0.012)
0.114 (0.117/0.111)
0.015 (0.021/0.009)
0.099 (0.096/0.103)
0.008 (0.006/0.010)
0.005 (0.005/0.005)
0.005 (n=1)
0.027 (0.039/0.015)
0.013 (0.016/0.009)
0.006 (0.006/0.007)
0.005 (0.004/0.007)
0.025 (0.022/0.028)
0.03 (0.042/0.017)
1.489 (1.917/1.060)
0.071 (0.088/0.054)
0.092 (0.071/0.028/0.179)
0.298 (0.448/0.148)
0.050 (n=1)
0.052 (0.093/0.011)
0.041 (0.038/0.044)
0.086 (0.034/0.137)
0.710 (1.050/0.370)
0.007 (0.005/0.01)
0.065 (0.059/0.080/0.055)
0.062 (0.039/0.085)
5.59 (5.7/5.4)
26.6 (21.6/31.6)
7.5 (6.7/8.4)
465
1266
833
>152.7
244.7
299.1
>38,175
48,940
1565
6128
>629
241
>6505
13,705
7652
279
17,940
42,725
>971
6209
11,000
739
>2166
5306
3133
9187
17,400
2620
7140
946
.
CH2CH2CO CH3
.
CH2CH2CO CH3
H
iso-Propenyl
.
CH2CH2CHOH CH3
171.6 (211.2/131.9)
>261.9 (n=2)
27.1 (59.9/11.1/10.4)
>240.7 (n=2)
246.7 (243.2/250.2)
160.7 (228.8/228.8/24.5)
64.1 (98.4/29.7)
179.4 (274.1/84.7)
170.9 (268.0/73.8)
>168.0
68.3 (56.4/80.2)
154.0 (226.4/217/4/18.3)
39.2 (43.5/35.0)
>247.2
79.6 (87.0/72.2)
>310.2
73.5 (38.2/108.8)
87.0 (10.5/163.4)
13.1 (n=1)
192.8 (205.3/180.3)
12.3 (12.2/12.3)
36.0/>241.8
>188.8
>242.42
123.3 (197.2/49.4)
215.5 (206.5/224.5)
>214.29
>229.02
57.7 (79.5/35.9)
133.7 (n=1)
18.7 (31.4/6.0)
21.6 (32.9/10.3)
6.44 (4.4/8.5)
.
CH2CH2CHOH CH3
H
Et
Et
Et
Et
Et
Et
.
CH2CO Ph
.
CH2CH(OH) Ph
.
(CH2)3CHOCO CH3
.
(CH2)4CHOCO CH3
(CH2)2OH
(CH2)3OH
(CH2)4OH
(CH2)4OH
(CH2)4OH
(CH2)4OH
(CH2)4OH
(CH2)6OH
(CH2)2CN
(CH2)2CN
(CH2)2CN
(CH2)2CN
(CH2)3CN
(CH2)4CN
(CH2)5CN
(CH2)6CN
(CH2)6CN
(CH2)3CN
iso-Propenyl
H
iPr
Et
CH2-4-C6H4-CN
iso-Propenyl
iso-Propenyl
H
iPr
Ph
iso-Propenyl
iso-Propenyl
iso-Propenyl
iso-Propenyl
iPr
(CH2)4CN
iso-Propenyl
H
>6000
>37,760
>9696
4110
144
>3018
>2489
193
CH2CH2CH2SO2CH3
CH2CH2CH2SO2CH3
CH2CH2CH2SO2CH3
CH2CH2CH2SO2CH3
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
CH2CH2CH(CH3)2
(CH2)4CN
(CH2)4OH
CO2Et
.
CO NH2
2674
359
526
74
162
2328
260
.
CO NHEt
.
CO NHPh
.
CO NHCH2Ph
.
CO CH3
115.6 (131.4/100.0)
16.3 (20.6/12.0)
16.9 (29.5/29.5/22.4)
27.1 (18.9/37.0)
SO2CH3
SO2CH(CH3)2
SO2N(CH3)2
437
a Values are the means of two experiments performed on consecutive weeks with the data from individual experiments shown in parentheses.
(NA=not active).
b CC50 refers to the concentration of drug causing a 50% reduction in cell viability in the absence of respiratory syncytial virus infection. Therapeutic
Index=CC50/EC50
.

1136
K.-L. Yu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1133–1137
iodogen. This chemistry was developed initially using a
structurally simple and chemically inert isoamyl side
chain, to afford 2l.
inhibitor. From the homologous series of nitriles
defined by 2ah and 2al–ao, it is evident that side chain
length exerts only a limited effect on potency since the
EC50 variation across this series is 5-fold with no clearly
discernible pattern. This effect appears to be reproduced
in the 2 i-Pr-substituted compounds 2aj and ap,
although this series was not examined as systematically
as the iso-propenyl homologues. For the series of alkyl
alcohol derivatives 2z–ag, antiviral activity potency
appears to be optimal with 3 and 4 CH2 units separating
the polar hydroxyl moiety from the heterocyclic
nucleus. The two diazirine-derivatives 2k and m pro-
vided potent antiviral agents, the result with 2m parti-
cularly gratifying since this molecule could readily be
labeled with 125I to furnish a photoaffinity agent with
the potential to provide more detailed insights into the
mode of action of this class of RSV fusion inhibitor at a
molecular level.28À30 From the limited comparisons
available, the diazirine side chain exhibits advantage
over the simpler isoamyl moiety.
The compounds that comprise this survey of benzimi-
dazol-2-one-derived RSV inhibitors were evaluated as
inhibitors of the cytopathic effect induced by the Long
(A) strain of RSV in the HEp-2 human lung epithelial
carcinoma cell line. The antiviral activity is reported as
an EC50, which represents the concentration of com-
pound required to provide 50% protection, and is com-
pared with the concentration of compound that causes
cytotoxicity to uninfected HEp-2 cells. The results are
compiled in Table 1 where the therapeutic index is cal-
culated as the ratio of CC50 to EC50.
The survey delineated by the examples compiled in
Table 1 establishes the viability of the benzimidazol-2-
one moiety as a scaffold from which potent RSV inhi-
bitors can readily be derived. The benzimidazol-2-one
moiety provides an opportunity to probe a vector una-
vailable to the benzotriazole ring system by modulating
the N substituent. In general, when the urea nitrogen is
substituted, this heterocycle provides a potency advan-
tage that can be substantial when compared to similarly
substituted benzotriazole derivatives described earlier.1
The nature and scope of the benzimidazol-2-one N
substituents examined in Table 1 were selected to pro-
vide not only insight into basic aspects of structure–
activity correlates, but were also designed to incorporate
structural elements and substituents capable of addi-
tional functionalization and modification. This formed
the basis of a broader campaign to obtain a suitable
compromise between antiviral potency and physical
chemical properties that would allow evaluation in ani-
mal models of infection. The unsubstituted benzimida-
zole 2a is 40-fold more potent than the analogous N-1
substituted benzotriazole,1 providing an initial indica-
tion of the superior intrinsic potency associated with the
N-substituted benzimidazolone heterocycle. Whilst 2a
demonstrates respectable inhibitory activity, it was
anticipated based on the earlier studies that the intro-
duction of an isoamyl side chain element would enhance
potency. This expectation was indeed realized with 2b,
which is over 2 orders of magnitude more potent than
2a and more than 10-fold better than the best benzo-
triazole derivative examined.1 Within the context of the
interrogation of isoamyl derivatives defined by 2b–j, 2l,
2n–q, and 2av–bd, it is readily apparent that the range of
N substituents compatible with potent RSV inhibition is
quite expansive, providing ample opportunity for struc-
tural variation and manipulation. The excellent activity
intrinsic to prototype 2c is readily improved by sub-
stitution of the benzimidazol-2-one N atom with struc-
turally simple alkyl and alkenyl groups (2b, d, and e),
alkyl nitriles that exhibit little dependence on chain
length (2f–i), functionalized benzyl derivatives (2j, l, and
n–q) and several polar, electron withdrawing sub-
stituents (2av–bd).
The safety margin for this series of RSV inhibitors, as
determined by the therapeutic index, ranges from 10
for a to 48940 for 2r. Three compounds, 2a, p, and az,
demonstrated measurable cytotoxicity towards the host
cell line at concentrations of less than 10 mM. Never-
theless, the high intrinsic antiviral potency associated
with 2n and p result in a significant therapeutic index. In
general, the safety margin for this series of RSV inhibi-
tors series is acceptable with no obvious patterns based
on overall lipophilicity, a documented correlate with
cytotoxicity.31
In summary, the data presented in Table 1 establish the
benzimidazol-2-one moiety as an effective structural
background for the generation of potent inhibitors of
RSV and both broadens and extends structure–activity
relationships for this chemotype.1 The availability of an
additional structural vector unavailable to the benzo-
triazole prototypes has provided significant potency
advantage and there is broad tolerance for functionality
in this region of the pharmacophore. Structural evolu-
tion of the benzimidazol-2-one class of RSV inhibitor
towards compounds that demonstrate antiviral activity
in animal models of RSV infection will be described in
due course.
Acknowledgements
We would like to thank Drs. Kim Wright and Richard
J. Colonno for their support and encouragement
throughout this work.
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